PD-L1-Binding Antigen Presenters: Redirecting Vaccine-Induced Antibodies for Cancer Immunotherapy.

The efficacy of immunotherapy in enhancing antitumor immunity in solid tumors remains limited, primarily due to the insufficient immunogenicity of tumor cells. In contrast, vaccination and natural viral infections can generate durable, high-titer antiviral antibodies. A modular Programmed Death-Ligand 1 (PD-L1)-binding antigen presenter (PBAP) has been engineered to tether varicella-zoster virus (VZV) glycoprotein E (gE) to PD-L1 expressed on tumor cell surfaces. This innovative construct leverages pre-existing anti-gE antibodies to trigger antibody-dependent effector mechanisms. PBAP-gE effectively bound to PD-L1 positive tumor cells and, together with vaccine-induced anti-gE antibodies, potentiated NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro and induced significant tumor regression in murine models. The PBAP platform is modular and versatile. For example, a PBAP-HER2 construct synergized with Herceptin and Kadcyla to eliminate human epidermal growth factor receptor 2 (HER2)-negative, PD-L1 positive cells. This work represents an innovative strategy for enhancing PD-L1-targeted therapies by leveraging pre-existing antibodies induced by vaccination or natural viral infections, alongside commercially available antibody-based therapies. Given the broad expression of PD-L1 across various solid tumors and hematologic malignancies, our strategy holds promise as a potentially widely applicable platform for diverse PD-L1-positive patient populations.